Process for production cilostazol

ABSTRACT

The present invention provides a process for producing cilostazol ÄIÜ in a high yield and a high purity, by reacting a carbostyril derivative ÄIIÜ with a tetrazole derivative ÄIIIÜ in the presence of an inorganic basic compound in a solvent of water, wherein water is used in an amount of 3 to 7-fold weight to that of the carbostyril derivative ÄIIÜ and the inorganic basic compound is used in an amount of 1 to 6 mol per mol of the carbostyril derivative ÄIIÜ. The process of the present invention is the improved and environment-friendly process for producing cilostazol being useful for pharmaceuticals. &lt;CHEM&gt;

TECHNICAL FIELD

[0001] The present invention relates to a novel process for producingcilostazol represented by the following formula [I]:

BACKGROUND ART

[0002] Cilostazol, prepared according to the present invention, whosechemical name is6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril, isknown to be useful as an antithrombotic agent, a cerebral circulationimprover, an anti-inflammatory agent, an antiulcer agent, a hypotensiveagent, an antiasthmatic agent, and a phosphodiesterase inhibitor, etc.(see e.g. JP-A-56-49378).

[0003] As for the process for producing cilostazol, it is known aprocess comprising a reaction of a carbostyril derivative represented bythe following general formula [II]:

[0004] with a tetrazole derivative represented by the following generalformula [III]:

[0005] (wherein X represents a halogen atom), in the presence of aninorganic base or an organic base (see e.g. JP-A-56-49378 and Chem.Pharm. Bull., 31(4), 1151-1157 (1983)).

[0006] According to the above-mentioned known process, the yield ofcilostazol is as low as about 50 to 74%, because there is also formed acompound in which the tetrazole derivative of general formula [III] hasreacted not only with the hydroxyl group of the carbostyril derivativeof general formula [II] but also with the 1-position of the cilostazol[I] simultaneously. The thus formed contaminative impurity, i.e. thecompound in which the 1-position of the cilostazol [I] is substituted bythe tetrazole derivative of general formula [III], is difficult toremove. Accordingly, there is a disadvantage of the known process thatthe production of the cilostazol with a high purity has required acomplicated process of purification.

[0007] Another process for producing cilostazol, it is known a processcomprising a reaction of the above-mentioned carbostyril derivative ofthe formula [II] with the above-mentioned tetrazole derivative of theformula [III], in the presence of a phase transfer catalyst (see e.g.JP-A-2001-213877 and WO 02/14283).

[0008] Yet another process for producing cilostazol, it is proposed aprocess comprising a reaction of the above-mentioned carbostyrilderivative of the formula [II] with the above-mentioned tetrazolederivative of the formula [III], in a non-aqueous hydroxylic solvent inthe presence of two kinds of basic compound or in a non-aqueous solventin the presence of molecular sieves to scavenge water formed as abyproduct (see e.g. WO 02/14283).

[0009] However, these known processes inevitably use undesirablematerials such as organic solvents and reagents in view of environmentalhygiene. On the basis of the growing conscious to internationalenvironmental conservation in recent years, great demands become arisenin a chemical industry to make every effort decreasing use of thesolvents and reagents pointed out the harmfulness, and preventing thosematerials from discharging into the environment. In order to fulfilthose demands, established processes have to be down for aconsideration, alternative raw materials, reagents and solvents beingless harmful have to be found out, and the processes having higherconversion rate, yield and selectivity have to be developed; so that theenvironmental load can be diminished.

[0010] Under the circumstances with these social demands, the presentinventors have made a study of the process being safer for theenvironment, for producing cilostazol with using water as a solvent inplace of an organic solvent. Heretofore, the chemical reaction has beenconsidered to be efficiently proceeding in the system wherein thereactive substances are dissolved. On the study of the process forproducing cilostazol so far, water has never been used as a solvent,since the tetrazole derivative of the formula [III] is absolutelyinsoluble in water and the tetrazole derivative of the formula [III] isexpected to be decomposed in water.

[0011] On the other hand, in view of the above-mentioned demands for theenvironmental hygiene, the present inventors have conducted furtherstudies with the aim of establishing the process using water as asolvent by all means. As a result, the present inventors have found thatthe objective process is established by applying the specificconditions, and thereby the objects of the present invention can beachieved. Based on this finding, the present invention has beenaccomplished.

DISCLOSURE OF THE INVENTION

[0012] According to the studies made by the present inventors, it hasbeen found that, by using water as a solvent in an amount of 3 to 7-foldweight to that of carbostyril derivative of the formula [II] and byusing inorganic basic compounds in an amount of 1 to 6 molar quantityper mol of carbostyril derivative of the formula [II], the reaction forproducing cilostazol may proceed without decomposition of the tetrazolederivative of the general formula [III], and besides the formation ofthe compound in which the 1-position of cilostazol is substituted by thetetrazole derivative of general formula [III] may be suppressed.

[0013] That is, the object of the present invention is to provide animproved process for producing the objective cilostazol with high yieldand purity, by the reaction of the carbostyril derivative of the formula[II] with the tetrazole derivative of the formula [III], in water as asolvent at the amount of 3 to 7-fold weight to that of carbostyrilderivative of the formula [II], in the presence of inorganic basiccompounds at the amount of 1 to 6 molar quantity per mol of carbostyrilderivative of the formula [II].

[0014] Accordingly, it is the object of the present invention to providea process for producing cilostazol, as a process being safe forenvironment. It is another object of the present invention to provide aprocess for producing cilostazol at a low cost and by a simpleprocedure. It is yet another object of the present invention to providea process for producing cilostazol without any complicated process ofpurification, in a high yield, and in a high purity. It is yet anotherobject of the present invention to provide an industrially advantageousprocess for producing cilostazol.

[0015] According to the process of the present invention, by usingenvironment-friendly water as a solvent, the objective cilostazol can beproduced on an industrial scale, at a low cost, by a simple procedure,in a high yield and in a high purity. Thus, the process of the presentinvention is of great worth as a process for producing cilostazol beinguseful for pharmaceuticals industrially.

BEST MODE FOR CARRYING OUT THE INVENTION

[0016] The improved process for producing cilostazol of the presentinvention is further explained in detail below.

[0017] The process of the present invention is indicated as thefollowing reaction scheme-1.

[0018] (wherein X is a halogen atom selected from the group consistingof a fluorine atom, a chlorine atom, a bromine atom and an iodine atom,among which particularly preferred is a chlorine atom).

[0019] In the reaction scheme-1, the reaction between a carbostyrilderivative of the formula [II] and a tetrazole derivative of the generalformula [III] is carried out in water at the amount of 3 to 7-foldweight to that of carbostyril derivative of the formula [II], in thepresence of inorganic basic compounds at the amount of 1 to 6 molarquantity per mol of carbostyril derivative of the formula [II].

[0020] As the inorganic basic compound, known ones can be usedextensively. Examples thereof include inorganic bases such as sodiumhydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide,sodium carbonate, potassium carbonate, cesium carbonate, lithiumcarbonate, lithium hydrogen carbonate, sodium hydrogen carbonate,potassium hydrogen carbonate, silver carbonate and the like; alkalimetals such as sodium, potassium and the like; and mixtures thereof. Incase of using one kind of inorganic basic compound alone, any one of thealkaline metal carbonates selected from the group consisting of sodiumcarbonate, potassium carbonate, cesium carbonate, lithium carbonate,lithium hydrogen carbonate, sodium hydrogen carbonate, potassiumhydrogen carbonate and the like is particularly preferred, and thepreferable amount thereof is 1 to 6 mol per mol of the carbostyrilderivative [II], particularly preferable 1 to 5 mol per mol of thecarbostyril derivative [II]. In case of using two or more kinds ofinorganic basic compound by mixture, a mixture of one or two or morealkaline metal hydroxides selected from the group consisting of sodiumhydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide andthe like; and one or two or more alkaline metal hydroxides selected fromthe group consisting of sodium carbonate, potassium carbonate, cesiumcarbonate, lithium carbonate, lithium hydrogen carbonate, sodiumhydrogen carbonate, potassium hydrogen carbonate and the like isparticularly preferred. In case of using the mixture, the amount of thealkaline metal hydroxide to be used is 0.4 to 1 mol, preferably 0.4 to0.9 mol per mol of the carbostyril derivative [II], and the amount ofthe alkaline metal carbonate to be used is 1 to 5 mol, preferably 2 to 5mol per mol of the carbostyril derivative [II]. When using the mixture,the total amount of the inorganic basic compounds is usually 1 to 6 mol,preferably 1 to 5 mol per mol of the carbostyril derivative [II].

[0021] The reaction is carried out usually at a temperature not lowerthan ambient temperature and not higher than 200° C., and preferably ata temperature of 50 to 150° C. The reaction time is usually from aboutone hour to about 20 hours. It is recommended to use the tetrazolederivative [III] usually in an amount of at least 0.5 mol, preferably0.5 to 1.5 mol, and more preferably 1.1 to 1.5 mol per mol of thecarbostyril derivative [II].

[0022] In the above-mentioned reaction, a lower alcohol may be added tothe reaction system in a certain amount thereof which does not affectenvironment. For example, a lower alcohol such as methanol, ethanol,propanol, isopropyl alcohol, butanol, ethylene glycol or the like may beadded in an amount of 5 to 30% by volume to the amount of water.Further, sodium sulfite, sodium thiosulfate or the like may be added tothe reaction system of the above-mentioned reaction for the purpose ofpreventing the coloration caused by oxidation.

[0023] The reaction may be carried out with circulating the reactionmixture by continuous disperser. The reaction mixture is repeatedlyintroduced into the continuous disperser and pulverized therein, thenreturned to the reaction vessel so as to circulate the reaction mixtureconstantly. The circulation of the reaction mixture can prevent thecrystals of the objective product of cilostazol from adhering with eachother to make big agglomerates.

[0024] Cilostazol of the formula [I] obtained by the above-mentionedreaction can be easily isolated by the conventional separating means. Assaid separating means, mention can be made of, for example, methodcomprising cooling the reaction mixture, followed by collecting thecrystals by filtration; method comprising heating the crystals andwashing it with alcohol such methanol or the like, followed bydistilling off the solvent and cooling so as to obtain the crystals;extraction method using a solvent; dilution method; recrystallizationmethod; column chromatography; preparative thin layer chromatography;etc.

EXAMPLES

[0025] Next, the process of the present invention is more specificallyexplained below with reference to examples.

[0026] The purity of the products obtained in the examples wasdetermined by high performance liquid chromatography (HPLC) under thefollowing conditions.

[0027] Detector: Ultraviolet rays absorptiometer

[0028] Column: equivalent of YMC-pack SIL 120A

[0029] Eluent: CH₂Cl₂:n-hexane:MeOH=20:10:1

[0030] Flow rate: about 1.0 ml/min.

[0031] Wavelength detected: 254 nm

Example 1

[0032] Into a reaction vessel having a capacity of 500 mL wereintroduced 6-hydroxy-3,4-dihydrocarbostyril (30 g, 0.18 mol),1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole (49.09 g, 0.20 mol, 1.1M), potassium carbonate (55.90 g, 0.40 mol, 2.2 M), sodium hydroxide(5.88 g, 0.15 mol, 0.8 M), sodium sulfite (1.5 g, 0.01 mol) and purifiedwater (150 ml). The mixture of the reactants was heated at about 92° C.for about 6 hours with circulating by continuous disperser (pipelinehomomixer T.K.ROBO MIX manufactured by TOKUSHUKIKA KOGYO CO. LTD.).After the completion of the reaction, the reaction mixture was cooled toaround 50° C., and the mixture was introduced into a flask having acapacity of 1 L, methanol (150 mL) was added thereto and the resultingreaction mixture was refluxed with heating for about 2 hours. Themixture was cooled to the ambient temperature and the precipitatedcrystalline product was collected by filtration and washed with purifiedwater (150 mL), methanol (90 mL), followed by purified water (150 mL),then dried at about 80° C. Thus, 62.14 g of cilostazol was obtained.Yield: 91.48%, Purity: 99.66%, m.p.: 158-159° C.

Example 2

[0033] Into a flask having a capacity of 200 mL were introduced6-hydroxy-3,4-dihydrocarbostyril (12 g, 0.07 mol),1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole (19.64 g, 0.08 mol),potassium carbonate (22.36 g, 0.16 mol), sodium hydroxide (2.35 g, 0.05mol), sodium sulfite (0.6 g, 0.004 mol) and purified water (60 mL). Themixture of the reactants was heated at about 92° C. for about 6 hours.After the completion of the reaction, the reaction mixture was cooled toaround 50° C., and the deposited crude crystals were once collected byfiltration. The crystals obtained were introduced into a flask andpurified water (120 mL) was added thereto, then the crystals were washedwith stirring at about 85° C. for about 15 minutes. The reaction mixturewas cooled to around 50° C., and the precipitated crystals werecollected by filtration. The crystals obtained were introduced into aflask again and methanol (84 mL) was added thereto, then the crystalswere washed with stirring at about 25° C. for about 15 minutes. Thereaction mixture was cooled to 10° C. or less, the precipitatedcrystalline product was collected by filtration and washed with methanol(24 mL), then dried at about 80° C. Thus, 24.15 g of cilostazol wasobtained. Yield: 88.88%, Purity: 99.50%, m.p.: 158-159° C.

Example 3

[0034] Into a reaction vessel having a capacity of 500 mL wereintroduced 6-hydroxy-3,4-dihydrocarbostyril (30 g, 0.18 mol),1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole (49.1 g, 0.20 mol, 1.1M), potassium carbonate (83.84 g, 0.61 mol, 3.3 M), sodium sulfite (1.5g, 0.01 mol) and purified water (150 mL). The mixture of the reactantswas heated at about 85° C. for about 6 hours with circulating bycontinuous disperser (pipeline homomixer T.K.ROBO MIX manufactured byTOKUSHUKIKA KOGYO CO. LTD.). After the completion of the reaction, thereaction mixture was cooled to around 50° C. and the deposited crudecrystals were once collected by filtration. The crystals obtained wereintroduced into a flask having a capacity of 1 L and purified water (300mL) was added thereto, then the crystals were washed with stirring atabout 85° C. for about 15 minutes. After washing the crystals, thereaction mixture was cooled to around 50° C. and the precipitatedcrystals were collected by filtration. The crystals obtained wereintroduced into a flask again and methanol (210 mL) was added thereto,then the crystals were washed with stirring at about 25° C. for about 15minutes. The reaction mixture was cooled to 10° C. or less, theprecipitated crystalline product was collected by filtration and washedwith methanol (60 mL), then dried at about 80° C. Thus, 62.79 g ofcilostazol was obtained. Yield: 92.44%, Purity: 99.61%, m.p.: 158-159°C.

Example 4

[0035] Into a flask having-a capacity of 200 ml were introduced6-hydroxy-3,4-dihydrocarbostyril (12 g, 0.07 mol),1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole (19.64 g, 0.08 mol, 1.1M), potassium carbonate (33.54 g, 0.24 mol, 3.3 M), sodium sulfite (0.6g, 0.004 mol) and purified water (60 mL). The mixture of the reactantswas heated at about 85° C. for 6 hours. After the completion of thereaction, the reaction mixture was cooled to around 50° C., and theprecipitated crystals were collected by filtration. The crystalsobtained were introduced into a flask, and purified water (120 mL) wasadded thereto, then the crystals were washed with stirring at about 85°C. for about 15 minutes. After washing the crystals, the reactionmixture was cooled to around 50° C. and the precipitated crystals werecollected by filtration. The crystals obtained were introduced into aflask again and methanol (84 mL) was added thereto, and the crystalswere washed with stirring at about 25° C. for about 15 minutes. Thereaction mixture was cooled to 10° C. or less, the precipitatedcrystalline product was collected by filtration and washed with methanol(24 mL), then dried at about 80° C. Thus, 24.28 g of cilostazol wasobtained. Yield: 89.36%, Purity: 99.44%, m.p.: 158-159° C.

Example 5

[0036] Into a flask having a capacity of 200 ml were introduced6-hydroxy-3,4-dihydrocarbostyril (12 g, 0.07 mol),1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole (19.64 g, 0.08 mol),potassium carbonate (22.36 g, 0.16 mol), sodium hydroxide (2.35 g, 0.05mol), sodium sulfite (0.6 g, 0.004 mol), purified water (36 mL) andisopropanol (3.6 mL), and the reaction was conducted for about 6 hoursunder reflux. After the completion of the reaction, the reaction mixturewas cooled to around 10° C., and the precipitated crystals werecollected by filtration. The crystals obtained were introduced into aflask, and purified water (120 mL) was added thereto, then the crystalswere washed with stirring at about 85° C. for about 15 minutes. Thereaction mixture was cooled to around 50° C. and the precipitatedcrystals were collected by filtration. The crystals obtained wereintroduced into a flask again and methanol (84 mL) was added thereto,then the crystals were washed with stirring at about 25° C. for about 15minutes. The reaction mixture was cooled to 10° C. or less, theprecipitated crystalline product was collected by filtration and washedwith methanol (24 mL), then dried at about 80° C. Thus, 24.31 g ofcilostazol was obtained. Yield: 89.47%, Purity: 99.45%, m.p.: 158-159°C.

1. A process for producing cilostazol represented by the followinggeneral formula [I]:

which comprises reacting a carbostyril derivative represented by thefollowing general formula (II):

with a tetrazole derivative represented by the following general formula(III):

(wherein X represents a halogen atom), in the presence of an inorganicbasic compound in a solvent of water, wherein water is used in an amountof 3 to 7-fold weight to that of the carbostyril derivative [II] and theinorganic basic compound is used in an amount of 1 to 6 mol per mol ofthe carbostyril derivative [II].
 2. The process according to claim 1,wherein said inorganic basic compound is selected from the groupconsisting of inorganic bases of sodium hydroxide, potassium hydroxide,cesium hydroxide, lithium hydroxide, sodium carbonate, potassiumcarbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogen carbonate, potassium hydrogen carbonate andsilver carbonate; alkali metals of sodium and potassium; and mixturesthereof.
 3. The process according to claim 2, wherein said inorganicbasic compound is one kind of alkaline metal carbonate selected from thegroup consisting of sodium carbonate, potassium carbonate, cesiumcarbonate, lithium carbonate, lithium hydrogen carbonate, sodiumhydrogen carbonate and potassium hydrogen carbonate.
 4. The processaccording to claim 2, wherein said inorganic basic compound is a mixtureof one or two or more alkaline metal hydroxides selected from the groupconsisting of sodium hydroxide, potassium hydroxide, cesium hydroxideand lithium hydroxide; and one or two or more alkaline metal carbonatesselected from the group consisting of sodium carbonate, potassiumcarbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.5. The process according to claim 4, wherein the amount of said alkalinemetal hydroxides to be used is 0.4 to 1 mol per mol of the carbostyrilderivative [II], and the amount of said alkaline metal carbonates to beused is 1 to 5 mol per mol of the carbostyril derivative [II].
 6. Theprocess according to claim 1, wherein the amount of the tetrazolederivative [III] to be used is at least 0.5 mol per mol of thecarbostyril derivative [II].
 7. The process according to claim 1,wherein X is a chlorine atom.